Mysterious Brain Clumps Behind Dementia Identified

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Certain forms of dementia may be caused by a gene mutation that
makes proteins in the brain clump together, a new study finds.

The most common cause of frontotemporal dementia and a motor
neuron disease called amyotrophic lateral sclerosis (ALS, or
Lou
Gehrig's disease ) is a genetic mutation that creates extra
copies of a DNA sequence, but the actual mechanism of the
diseases is unknown. A team of researchers has now found that
proteins, molecules that normally help cells function, are being
produced from the mutated gene and appear to be causing the
clumping seen in both those diseases.

The findings, described online today (Feb. 7) in the journal
Science, could explain how these diseases arise and might even be
treated.

About 10 percent of FTLD (frontotemporal lobar degeneration) and
ALS patients have a mutation in the C9orf72 gene, which contains
a short repeated DNA sequence. Healthy people have about 25
repeats of this sequence, but there are hundreds of repeats in
these patients. Their brains exhibit telltale clumps of proteins
in the hippocampus and cerebellum regions.

While proteins
in other forms of dementia are known, patients with this
mutation have clumps of other, unknown proteins, said study
co-author Dieter Edbauer, a neuroscientist at Ludwig Maximilian
University of Munich, in Germany. The mutated gene lacks the
label that normally tells cells to start making a protein, and is
located in a stretch of the DNA that isn't normally active.

Protein mystery

Edbauer and his colleagues hypothesized that if the gene were
somehow activated, it would cause three different proteins to be
made, and these proteins would aggregate in cells and cause
disease.

To test their hypothesis, the researchers took both diseased and
healthy brain tissue from deceased patients and filtered it
through a fine mesh. Clumps of brain tissue from the patients got
stuck in the mesh. By making antibodies (proteins produced by the
body to target and fight off foreign invaders) that recognized
the three specific proteins, the scientists were able to
determine that these were the proteins in the clumps.

"This study helps to resolve a major question about how C9orf72
mutations cause FTD and ALS," said neurologist Adam Boxer of the
University of California, San Francisco, who was not involved in
the study.

"It suggests that these mutations can lead to creation of a new
toxic protein that aggregates and accumulates in cells, similar
to other
neurodegenerative diseases such as Huntington's and
Alzheimer's, which are also associated with toxic protein
aggregates," Boxer told LiveScience. [ 10
Odd Facts About the Brain ]

Others agree that the findings, if replicated, will be important.
"It would be good to confirm their results using an independent
method," said neuropathologist Ian Mackenzie of Vancouver General
Hospital and the University of British Columbia, in Canada.

Understanding the diseases

There are several possible explanations for how the proteins are
being made. One is that the ribosome, the cellular machinery that
reads genetic instructions to make proteins, is misreading the
mutated gene. Another possibility is that the repeated sequence
is forming a hairpin shape that attracts the ribosome and tells
it to make proteins.

It's unclear whether the clumps are causing the diseases or are
simply markers. If the protein clumps are in fact responsible,
scientists might be able to treat the disease by getting rid of
those proteins, Edbauer said.

FTD and ALS are characterized by personality changes, language
abnormalities and movement disorders, which often appear before
the age of 65. There is currently no cure.